Genome-Wide Identification of Human FOXP3 Target Genes in Natural Regulatory T Cells

Sadlon, Timothy; Wilkinson, Bridget G.; Pederson, Stephen; Brown, Cheryl Y.; Bresatz, Suzanne; Gargett, Tessa; Melville, Elizabeth; Peng, Kaimen; D’Andrea, Richard J.; Glonek, Gary; Goodall, Gregory J.; Zola, Heddy; Shannon, M. Frances; Barry, Simon C.

doi:10.4049/jimmunol.1000082

Cited by 129 publications

(169 citation statements)

References 88 publications

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“…Type 1 diabetes is an example of a disease which arises as a result of complex interactions between genetic and environmental factors conspiring to drive disease progression. A meta‐analysis of six genome‐wide association studies to identify single nucleotide polymorphisms that track with type 1 diabetes identified 45 loci,27 and using our FOXP3 ChIP data,28 we observed that 34 (75%) contain a FOXP3 binding site. A more recent fine mapping of genetic risk of type 1 diabetes identified 51 distinct loci, of which 34 mapped to a gene 29.…”

Section: Treg and Diseasementioning

confidence: 74%

“…As well as identifying a significant number of loci both directly bound by FOXP3 and associated with differentially expressed genes in Treg, many loci were identified that are either too far from a transcription start site to annotate to a target gene easily, or do not appear to be associated with differentially expressed genes in Treg. For example, in our human FOXP3 ChIP data set, of almost 3000 FOXP3‐bound regions, only 750 were also annotated to genes differentially expressed in human Treg28 (Figure 1). This has revealed a core network of genes that are tightly regulated by FOXP3 and has also identified significant bioinformatic limitations in annotation of FOXP3‐bound regions.…”

Section: Transcriptional Control Of Treg Formation and Functionmentioning

confidence: 99%

“…The modifiable mediators of this regulation include methylation,37, 38, 39, 40, 41, 42, 43, 44 acetylation45, 46, 47 and microRNA‐mediated control of transcript translation 28, 48, 49, 50, 51, 52, 53, 54, 55. The global regulation of FOXP3 is influenced by chromatin organises, including SATB1 acts both during development and in mature cells 48, 58.…”

Section: Foxp3 Epigenetic Regulationmentioning

confidence: 99%

“…Of the 2000‐3000 target genes identified by FOXP3 ChIP,28, 83 a subset are directly differentially expressed or repressed in Treg at any given time, including SATB148 (Figure 1). These genes combine with FOXP3 to form the FOXP3 gene regulatory network and shape the function of Treg.…”

Section: Microrna‐mediated Tuning Of Regulatory Phenotypementioning

confidence: 99%

“…Genome‐wide molecular approaches are being utilised to identify the key genes and gene regulation interactions in human Treg, including ChIP, iCLIP and expression profiling, and this aides understanding Treg function and stability. We have previously demonstrated that miRNAs, such as miR‐155, and FOXP3 cooperate to coordinately regulate other key genes in Treg, including SATB148 and ZEB228 (Figure 3), and have identified a number of other candidate miRNAs involved in the Treg genotype. It is interesting to observe that a common miRNA/FOXP3‐mediated molecular switch is able to regulate several key genes, which forms a core part of the FOXP3 gene regulatory network (GRN).…”

Section: Foxp3 Cooperates With Micrornas Via Regulatory Loops Which Tmentioning

confidence: 99%

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Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

et al. 2018

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Regulatory T cells (Treg) are critical for preventing autoimmunity and curtailing responses of conventional effector T cells (Tconv). The reprogramming of T‐cell fate and function to generate Treg requires switching on and off of key gene regulatory networks, which may be initiated by a subtle shift in expression levels of specific genes. This can be achieved by intermediary regulatory processes that include microRNA and long noncoding RNA‐based regulation of gene expression. There are well‐documented microRNA profiles in Treg and Tconv, and these can operate to either reinforce or reduce expression of a specific set of target genes, including FOXP3 itself. This type of feedforward/feedback regulatory loop is normally stable in the steady state, but can alter in response to local cues or genetic risk. This may go some way to explaining T‐cell plasticity. In addition, in chronic inflammation or autoimmunity, altered Treg/Tconv function may be influenced by changes in enhancer–promoter interactions, which are highly cell type‐specific. These interactions are impacted by genetic risk based on genome‐wide association studies and may cause subtle alterations to the gene regulatory networks controlled by or controlling FOXP3 and its target genes. Recent insights into the 3D organisation of chromatin and the mapping of noncoding regulatory regions to the genes they control are shedding new light on the direct impact of genetic risk on T‐cell function and susceptibility to inflammatory and autoimmune conditions.

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Section: Treg and Diseasementioning

confidence: 74%

Section: Transcriptional Control Of Treg Formation and Functionmentioning

confidence: 99%

Section: Foxp3 Epigenetic Regulationmentioning

confidence: 99%

Section: Microrna‐mediated Tuning Of Regulatory Phenotypementioning

confidence: 99%

Section: Foxp3 Cooperates With Micrornas Via Regulatory Loops Which Tmentioning

confidence: 99%

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Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

et al. 2018

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Encapsulation of Human Natural and Induced Regulatory T‐Cells in IL‐2 and CCL1 Supplemented Alginate‐GelMA Hydrogel for 3D Bioprinting

Kim

Hope

Gantumur

et al. 2020

Adv Funct Materials

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Regulatory T-cells (Tregs) are important modulators of the immune system through their intrinsic suppressive functions. Systemic adoptive transfer of ex vivo expanded Tregs has been extensively investigated for allogeneic transplantation. Due to the time-consuming and costly expansion protocols of Tregs, more targeted approaches could be beneficial. The encapsulation of human natural and induced Tregs for localized immunosuppression is described for the first time. Tregs encapsulated in alginate-gelatin methacryloyl hydrogel remain viable, phenotypically stable, functional, and confined in the structure. Supplementation of the hydrogel with the Treg-specific bioactive factors interleukin-2 and chemokine ligand 1 improves Treg viability, suppressive phenotype, and function, and attracts to the structure CCR8 + T-cells enriched with anti-inflammatory subpopulations, including Tregs, from human peripheral blood. Furthermore, these findings are applicable to 3D bioprinting. Co-axial printing of murine pancreatic islets with human natural and induced Tregs protects the islets from xenoresponse upon co-culture with human peripheral blood mononuclear cells. This establishes the co-encapsulation of Tregs by co-axial 3D bioprinting as a valid option for providing local immune protection to allogeneic cellular transplants such as pancreatic islets.

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Peptidase inhibitor 16 identifies a human regulatory T‐cell subset with reduced FOXP3 expression over the first year of recent onset type 1 diabetes

et al. 2019

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CD4+ T‐cell subsets play a major role in the host response to infection, and a healthy immune system requires a fine balance between reactivity and tolerance. This balance is in part maintained by regulatory T cells (Treg), which promote tolerance, and loss of immune tolerance contributes to autoimmunity. As the T cells which drive immunity are diverse, identifying and understanding how these subsets function requires specific biomarkers. From a human CD4 Tconv/Treg cell genome wide analysis we identified peptidase inhibitor 16 (PI16) as a CD4 subset biomarker and we now show detailed analysis of its distribution, phenotype and links to Treg function in type 1 diabetes. To determine the clinical relevance of Pi16 Treg, we analysed PI16+ Treg cells from type 1 diabetes patient samples. We observed that FOXP3 expression levels declined with disease progression, suggesting loss of functional fitness in these Treg cells in Type 1 diabetes, and in particular the rate of loss of FOXP3 expression was greatest in the PI16+ve Treg. We propose that PI16 has utility as a biomarker of functional human Treg subsets and may be useful for tracking loss of immune function in vivo. The ability to stratify at risk patients so that tailored interventions can be applied would open the door to personalised medicine for Type 1 diabetes.

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Genome-Wide Identification of Human FOXP3 Target Genes in Natural Regulatory T Cells

Abstract: Material Supplementary 2.DC1http://www.jimmunol.org/content/suppl/2010/06/16/jimmunol.100008

Cited by 129 publications

References 88 publications

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

Encapsulation of Human Natural and Induced Regulatory T‐Cells in IL‐2 and CCL1 Supplemented Alginate‐GelMA Hydrogel for 3D Bioprinting

Peptidase inhibitor 16 identifies a human regulatory T‐cell subset with reduced FOXP3 expression over the first year of recent onset type 1 diabetes

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